Clinical imaging technology plays a significant role in diagnosis of injuries and disease processes. Many parts of the human body can now be examined for diagnostic purposes using a variety of imaging techniques. Radiography has long been used to image body parts through which externally generated x-rays are transmitted. Computerized axial tomography (CAT) provides cross-sectional x-ray images of a plane of the body. Specific tissues or organs may be targeted in positron emission tomography (PET), single photon emission computed tomography (SPECT), and gamma scintigraphy. In PET, SPECT, and gamma scintigraphy, radiopharmaceutical agents capable of being sequestered (concentrated) to some degree in the target tissue or organ are internally administered to the patient, and images are generated by detecting the radioactive emissions from the concentrated radiopharmaceutical agent. Some of the radiopharmaceutical agents currently used for cardiovascular imaging include nuclides such as .sup.201 Tl, .sup.99m Tc, .sup.133 Xe, and the like; chelates of nuclides; radiolabeled metabolic agents such as .sup.11 C-deoxy-D-glucose, .sup.18 F-2-fluorodeoxy-D-glucose, [1-.sup.11 C]- and [.sup.123 I]-.beta.-methyl fatty acid analogs, .sup.13 N-ammonia, and the like; infarct avid agents such as .sup.99m Tc-tetracycline, .sup.99m Tc-pyrophosphate, .sup.203 Hg-mercurials, .sup.67 Ga-citrate, and the like; and radiolabeled ligands, proteins, peptides, and monoclonal antibodies. Whole cells such as erythrocytes, platelets, leukocytes, and other cells may also be labeled with a radionuclide and function as radiopharmaceutical agents.
The amount and type of clinical information that can be derived from PET, SPECT, and gamma scintigraphic images is related in part to the ability to concentrate the radiopharmaceutical agent in the target tissue or organ. Although many radiopharmaceuticals are available for clinical use, the resolution of the image generated may be limited depending on various factors. The resolution of a particular imaging agent for imaging diseased or injured tissue depends in part on the affinity of the radiopharmaceutical for the site of injury or disease as compared to its affinity for surrounding healthy tissue.
Radiopharmaceuticals are used in a variety of types of cardiovascular studies to obtain different kinds of information. For example, radiopharmaceutical agents used in cardiac blood flow and blood pool studies provide information on murmurs, cyanotic heart disease, and ischemic heart disease. Perfusion scintigraphy agents provide measurements of blood flow useful in detection of coronary artery disease, assessment of pathology after coronary arteriography, pre- and postoperative assessment of coronary artery disease, and detection of acute myocardial infarction. Infarct avid agents are used for "hot spot" infarct imaging. Radionuclide-containing antibodies directed against the heavy chain of cardiac myosin have been proposed to identify zones of acute myocardial necrosis, and .sup.99m Tc-labeled low density lipoprotein were proposed for detecting atheromatous lesions in their early stages after onset of endothelial damage.
Radiopharmaceutical ligands specific for .beta.-adrenergic receptors demonstrate uptake in lungs and do not show sufficient specificity for heart tissue, as reviewed in Elmaleh, D. R., et al., in Noninvasive Imaging of Cardiac Metabolism, E. E. van der Wall, ed. (Martinus Nijhoff, Boston, 1987) pp. 1-37. The same reference describes preliminary studies of labeled muscarinic receptor ligands for cardiac imaging which showed some specificity for heart. Studies using .sup.111 In-labeled insulin to image heart insulin receptors demonstrated less specificity for cardiovascular tissue.
Diadenosine 5', 5'", P.sup.1,P.sup.4 -tetraphosphate (Ap.sub.4 A) is an adenine analog which is ubiquitously present in living cells, appearing to play an important role in extracellular signaling events in a variety of tissues. In particular, Ap.sub.4 A is a competitive inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation, which occurs through the binding ADP to a specific class of purine receptors found on platelets and megakaryocytes. U.S. Pat. No. 5,049,550 discloses antithrombotic analogs of Ap.sub.4 A, the therapeutic efficacy of which is premised on the observation that thrombus (blood clot) formation includes an initial platelet aggregation step and on the hypothesis that inhibition of platelet aggregation will result in inhibition of clot formation. U.S. Pat. No. 5,219,841 discloses a pharmaceutical composition containing Ap.sub.4 A as its active ingredient, for treatment of heart disease. U.S. Pat. No. 5,380,715 discloses use of Ap.sub.4 A as a hypotensive agent, particularly in connection with surgical procedures which employ hypotensive anesthesia.
D. R. Elmaleh, et al. (1984) Proc. Natl. Acad. Sci. USA 81, 918-921 discloses .sup.99m Tc-labeled Ap.sub.4 A (.sup.99m Tc-Ap.sub.4 A) used to image tumors implanted into rats. The method used to chelate the .sup.99m Tc to the Ap.sub.4 A in this study yielded a mixture, in which .sup.99m Tc was attached to the Ap.sub.4 A-dinucleotide and which also may have contained unchelated .sup.99m Tc. This study was based on the premise that some human tumor cells are permeable to exogenous ATP and ADP, and that these cells incorporate the intact nucleotides in intracellular pools, in contrast to normal cells. Ap.sub.4 A was shown to permeate into hepatoma cells but not into a number of untransformed mammalian cell lines. In addition to accumulating in implanted tumors, the .sup.99m Tc-Ap.sub.4 A in the 1984 study also accumulated in kidney, liver, bone, muscle, and lung. No accumulation of .sup.99m Tc-Ap.sub.4 A in heart was observed in this study.